AM-101 TACTT1 Results Released

Good to have you back, @ResonanceCEO, you dropped off the radar for a while. I hope everything is going well for you.

 

Thanks! Doing great and its good to be back

 

So why does auris medical do clinical test for 1 year since onset? This is not a few weeks..

 

Because they don't really know when the efficacy drops off, actually. They are trying out up to 12 months because, according to them "They did not see a decrease in efficacy towards the end of the original three month window". They will want to have as broad of a market as possible for their eventual drug that they release.

The FDA is not allowing them to test up to 12 months in the US for some reason, they are limiting them to 3 months. I can't answer the reason for that though.

 

Thank you for answering. Because i would like engage clinical trials.. So i dont have too much time.. I suffered acoustic trauma on november 2013..

 

Hudson you may know more than me about this. Are they really trying to treat tinnitus 3 months out from the onset of tinnitus??? Do they have any positive clinical results for 3 months out? If they do, then that's very surprising.

 

I had my hearing tested two weeks ago. Everything is fine they say.

What makes you think AM101 won't work for people who's had it for longer than that? Auris Medical are now rolling out clinical trials for people who's had it for 1 year, I don't think they would do that unless they suspected it could work in chronic cases. What do you know that they don't? (sorry if i sound rude, that is not my intention! Just asking, i'm sure you understand!)

 

Yes, the drug is as good for people who's had it for 3 months as in people who's had it for 2 weeks. No decline in efficiency, which is why they're now extending the tinnitus-time-window in their new trials! :-D

 

I have spoken so several people who took part in the trial who all now have very faint tinnitus-- my question is how common is it for a person to have tonal t that they can hear relatively loudly (not just in silent rooms, but over TVs, walking down the street, etc)-- how common is it for that level of t to persist for 2-4 months and then just die to a faint sound that you can't even hear while laying in bed in a quiet room unless you look for it-- because that's how these people describe their current t

 

@ResonanceCEO I can't remember where I read it, but I know that I have read from press releases that there were no statistical differences in the positive outcomes for people who had started the treatment either very close to the onset of their tinnitus, or for those who were nearing the 3 month cut off. I'll dig around for it this evening when I have more time.

Are you going to attend Richard Tyler's University of Iowa tinnitus workshop this year? I was thinking about driving over and hitting it up for at least a day. It would be nice to meet you if you are there. I remember you had said you live in the Chicago area.

 

@Hudson I read one of your older posts where you said that you wanted to go to grad school to study smth connecting to tinnitus. Are you already doing that or planning to do that?

 

I could be wrong on this but I thought they they were gonna do 3+ months after the original within 3 months of onset and include those who had the placebo for the 3 months of onset trials. Ring any bells for anyone?

 

no there are two different study groups one 0-3 months and the other is 3-12 months.
then ther's another study which is a follow up study, in which the people
can participate that took part in any am-101 study. in that study AMPACT
there is just AM101

 

So I've reviewed some unread emails from Auris (the exact same info is on the Auris website as well). Remember when reading about any drug trials - approval is based on safety (will this drug hurt you) and efficacy (will this drug help you).

These are two different aspects of a drug trial, with safety arguably being the most important.

- regarding the lack of a statistically significant difference, that was related to adverse effects only, which means that AM101 is not more likely to make you worse than if you took placebo. This is part of the safety component.

- they say that they didn't have sufficient power to demonstrate difference in efficacy over placebo, which is not surprising considering there were only 85 patients. They could only demonstrate a trend towards positive outcomes, because there just weren't enough people treated.

- regarding whether they are treating people who are out of the acute phase or not, I suspect this is for two reasons: 1) they want to have more than 85 people in their trial, so they are casting a wider net. 2) they are wanting to further prove the safety of the drug in an even broader range of people, so that more patients can be treated in both later trials, and when it comes out on the market.

- In summary, this trial did not show whether AM101 worked or not. This is not bad because they only had 85 patients - it would have to be a truly astonishing drug in order for that to happen with a multifactorial disease process like T. Basically this trial was designed to prove that AM101 is not going to burn a hole in your ear or otherwise make your symptoms worse. The phase 3 clinical trials of 600 in the EU and 330 in the US should definitively show whether AM101 works for tinnitus or not. All of this a normal part of the drug approval process. Stay tuned!

I stand by my assertion that this drug should not work outside the acute phase of tinnitus based on what I understand of the science. However I'm keeping an open mind - maybe eliminating the cochlear component (as AM101 does) makes the brain component more tolerable. I think the expansion to other groups is about increasing this number of treatable patients, which is a perfectly reasonable thing to do.

I don't really go to a lot of workshops, those are generally aimed at either clinicians or patients. However there are plenty of people around me and on TT that let me know what's in the world of T.

 

If you get the time I was wondering if you could look this over and give your opinion. Its a animal study on rats with chronic tinnitus and seemed to have decent results. Same principle Am 101 uses i believe.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077674

 

If Am101 only works in acute cases, does that mean less people will get tinnitus, and people will stop working on a cure for chronic tinnitus? We will just be a forgotten group?

 

Interesting sentence from article:

The bilateral decrease, and its presence 8 weeks after discontinuation of D-AP5 treatment, support the hypothesis of a system reset to pre-exposure levels.

The main difference I can see is this nmda antagonist was being delivered to brain vs inner ear, correct?

 

From Auris Medical website:

Would AM-101 work only in acute tinnitus?

The animal studies with AM-101 were performed in a model of acute acoustic trauma with treatment shortly after tinnitus onset. It seems likely that after some time centralization of tinnitus sets in (i.e. the brain "memorizes" the phantom sound), and a pharmacological treatment of tinnitus in the inner ear may no longer be possible. This question is the subject of much scientific discussion. In general, brain plasticity tends to be more rapid in the type of animals tested than in humans. In the phase IIb trial, AM-101 was still effective after 3 months.




Why couldn't they just test it on a rat with chronic T as well? How can they so easily assume that it won't work in chronic cases? Doesn't the new trials with patiens >1 year suggest that they suspect it might work in chronic cases? Am I, who has very low tinnitus compared to other people, more likely to benefit, because low volume T means less "memorization" in the brain?

 

No, I honestly doubt that. First of all, AM-101 most likely will not cure people even that get it. Just reduce it. As a result, there will still be a large number of patients who end up having chronic tinnitus, adding to the already huge pool of people with chronic tinnitus. As @ResonanceCEO said above, AM-101 will probably be the first in a long line of drugs aimed at tinnitus and hearing loss. Once one company can get something to market and show that it is somewhat treatable, other companies are going to line up to get a ticket on the gravy train as well. Guaranteed.

 

So this is an NMDA receptor antagonist like AM101, however the primary objective of the paper was not to prove efficacy of a drug. The objective was to show what happens in the brain when you shut down tinnitus in the cochlea. The MEMRI technique is meant to help compare activity in the entire auditory system from the cochlear nerve to the the auditory cortex. This doesn't have much to do with T therapies outside of better defining how drug targets function. Anyway its a super- cool paper from a basic science perspective that I was not previously aware of. We were going to do the MEMRI imaging technique here for our experiments, but it turns out that the manganese deafens the animals, so its not good for long-term studies.

 

Seems to me unless anyone is privy to the results we just don't know yet whether am101 will work for those who have had T a while compared to those in the acute phase. However IF it's true that effectiveness does not drop off over 3 months that would at least offer realistic hope that it wouldn't drop off over a longer period if at all.

I know their website says it "seems likely" that the tinnitus "sets in" and the brain "memorises" the sound - but I'd want them to specify the exact mechanism by which that happens before buying into it. Maybe they have done so and I'm not aware of it but there are long term tinnitus sufferers whose T disappears and reappears - so clearly chronic tinnitus is not always on all the time.

 

Thanks for the quick response. I knew I was missing something, So to clarify the changes in the brain do not mean that the T was affected. Originally that was my impression. But why would the drug have affected the brain at all if it wasn't working on the T. Would this be because they way they administered the drug that it this affect. Sorry for all the questions Im just curious because I may be meeting with someone soon to discuss my participation in the trials, and you seem to have quite a bit of knowledge on it. Thanks In advance!

 

There are so many stories of people getting completely rid of tinnitus after many months that I believe it is bullshit. Just in my social circle there are people who told me "I had tinnitus for 6 months after an ear infection. Just listened to TV when going to bed and after 6 months it was gone"

And on reddit, people who had T due to neck issues etc, get rid of their 1 year old T when the neck issue resolved.

And tinnitus as low as mine, I don't think it will be a problem.. But of course that is wishful thinking.

I hope that if I get rid of T, that the sound sensitivity and middle ear muscle spasms will go away too. I think they will tho, as I think they are related to anxiety related to the attention I give to sound and the ears. It's as if my whole nervous system considers sound an enemy

 

I am no loner stressing about my T, and the spasms have reduced greatly and my sound sensitivity is almost completely gone. So I think there is a good chance those two things will subside.

 

What makes you say this - is it simply because of neural plasticity issues?

 

First thing to clarify is that there are no reliable animal models of tinnitus. We can guess or whatever, but we can't ask a rat if it has tinnitus. The point of this paper was show how the auditory system beyond the cochlea reacts to having the cochlea treated with an NMDA receptor antagonist. So cut off the input of the cochlea and then show activity in the rest of the auditory pathway. This is a basic science nerd's paper - i.e. only interesting to nerds like me. The real question is: how much of tinnitus is cochlear and how much is brain? Nobody has a great answer, and no study on a rat is going to clear that up, but it sure is interesting to map out the auditory pathway with manganese as these people have done. Either way, it should not affect your judgement of any clinical trial or affect your decision making process in any way.

 

Yeah basically. We are having a healthy discussion about it here in the lab as I write this, so clearly its not set in stone.

For me to answer your question fully would add lots and lots of confusion to the rest of the forum members that I'm pretty sure I'd never have an adequate explanation for. But the short answer is NMDA receptors are responsible for neural plasticity, so you're on the right track.

NMDA receptor antagonists (blockers) decrease the strength of a pathological neuronal connection like tinnitus.

Will these NMDA receptor blockers help?
Probably.

Will they cure T completely?
Probably not, because the central (brain) component will remain.

Is that good enough?
Judging by the suffering I see all over this forum, I think we'd all be happy with a little relief.

 

Chris

I know I asked you this earlier, but do you find it odd that these NMDA receptor blockers are still working to reduce the tinnitus signal 1.5-2 years after administration in individuals who appear to have been succesfully treated by AM-101? I don't know whether you would know this, but wouldn't the NMDA blockers work almost immediately in stopping the signal if they worked at all- do they work immediately in the treatment of other conditions-- the reason I ask is the people I have spoken to have noticed a gradual improvement after am-101 treatment, and that has always confused me and letft open the door, at least in my mind, that these people just habituated

 

Yes, I know most chronic tinnitus research focuses on how the brain maintains its self-sustaining network that keeps the tinnitus precept active.

But there's not enough studies--yet--to determine if the brain will slowly unwind its maladaptive plasticity once the aberrant signals from the cochlea no longer feed the auditory cortex. When you examine research on topics like rTMS, there seems to be a consensus that although auditory and non-auditory sections of the brain are affected, the hub of the brain's maladaptive plasticity emanates from the auditory cortex. Correcting the cochlea will starve the auditory cortex of its input, which may create a domino affect on other brain structures.

Please correct me if I'm wrong or elaborate on any of these ideas!

 

Of course, the strength of the signal, the coherence among brain areas involved in the tinnitus signal, and the duration of the tinnitus will undoubtedly affect whatever unwinding that may occur. But even these barriers may be surmounted with different therapeutic modalities focused on the brain.

I am encouraged, for example, by research being done into epilepsy--specifically the development of brain implants as well as "neural nets." And, of course, the current brain implants for tinnitus as well as the new clinical trial are all encouraging.

But I do prefer less invasive forms of neuromodulation! And the TRI and other researchers are working to improve their protocols. It's just that these technologies are several years away.